RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as mitoxantrone, etoposide, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with mitoxantrone, etoposide, and cytarabine in treating patients with relapsed or refractory acute myeloid leukemia.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8 and 11; and mitoxantrone IV, etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

Drug: bortezomib

Given IV

Other Names:

LDP 341

MLN341

PS-341

VELCADE

Drug: mitoxantrone hydrochloride

Given IV

Other Names:

CL 232315

DHAD

DHAQ

dihydroxyanthracenedione

mitoxantrone HCl

Novantrone

Drug: etoposide

Given IV

Other Names:

Demethyl Epipodophyllotoxin Ethylidine Glucoside

EPEG

epipodophyllotoxin

VePesid

VP-16

VP-16-213

Drug: cytarabine

Given IV

Other Names:

ARA-C

ARA-cell

arabinofuranosylcytosine

arabinosylcytosine

Cytosar-U

cytosine arabinoside

Other: flow cytometry

Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the DLT, MTD, and the recommended Phase 2 dose of bortezomib in combination with MEC in patients with relapsed/refractory AML.

SECONDARY OBJECTIVES:

I. To describe the non-dose limiting toxicities associated with bortezomib in combination with MEC in patients with relapsed/refractory AML.

II. To describe any preliminary evidence of clinical activity of this combination (CR rate) in relapsed/refractory AML.

III. To determine the median CD74 antigen expression in patients achieving a response versus those patients not achieving a response.

OUTLINE:

This is a dose-escalation study of bortezomib.

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8 and 11; and mitoxantrone IV, etoposide IV over 1 hour, and intermediate-dose cytarabine IV over 6 hours on days 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-5 weeks.

Eligibility

Ages Eligible for Study:

18 Years to 70 Years (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion

Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care

Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study; female subject is not lactating

Male subject agrees to use an acceptable method for contraception for the duration of the study

Relapsed or refractory AML (excluding acute promyelocytic leukemia), based on World Health Organization Classification; all other subtypes of AML will be eligible; refractory disease will be considered failure to respond to 2 cycles of induction chemotherapy (7+3 and 5+2); any number of relapses will be eligible

No evidence of leptomeningeal disease; a lumbar puncture does not need to be performed unless there is clinical suspicion of leptomeningeal disease

Patients with secondary AML, and patients with a prior autologous and allogeneic bone marrow transplant are eligible

Patients with an allogeneic transplant must meet the following conditions: the transplant must have been performed more than 90 days before registration to this study, the patient must not have >= Grade 2 acute graft versus host disease (GvHD), or either moderate or severe limited chronic GvHD, or extensive chronic GvHD of any severity; the patient must be off all immunosuppression for at least 2 weeks

No uncontrolled infections

No history of hypersensitivity to boron or mannitol

No known history of HIV or active hepatitis B or C

No major surgery within 4 weeks prior to trial enrollment

Exclusion

Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant

Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment

Female subject is pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women

Patient has received any standard or investigational therapy for their leukemia within 14 days before enrollment (except for hydrea)

Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Patients with prior malignancy are eligible; however, the patient must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy at least 6 months prior to registration and all treatment-related toxicities must have resolved

Leptomeningeal/ central nervous system involvement with AML; a lumbar puncture does not need to be performed unless there is clinical suspicion

Patients who have had prior pulmonary radiation

Prohibited Concurrent Therapy: any investigational agent other than VELCADE; G-CSF and GM-CSF are not allowed

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01127009